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Principal Investigator: Roger Bedimo
Organization: VA NORTH TEXAS HEALTH CARE SYSTEM
Fiscal Year: 2024
Funding agency: Veterans Affairs
Neurologic symptoms are among the most common post-acute sequelae of COVID-19 (PASC). Recent
studies show that there is a very high rate of neurocognitive changes among Veterans surviving acute COVID-
19 infection. The long-term neurocognitive changes of this infection could be even worse and remains
incompletely characterized. Moreover, neurological sequelae have been considered the most disabling of the
long-term complications. Possible mechanisms of neuronal damage from SARS CoV-2 infection include direct
viral CNS invasion through the cribriform plate or hematogenous route, or retrograde neuronal dissemination,
or indirect injury mediated by systemic inflammation, and secondary degenerative mechanisms. Whether
neurocognitive changes can be predicted by biomarkers – or imaging evidence of – inflammation, neuronal
damage or disruption of blood brain barrier has never been evaluated in a well-characterized cohort.
Furthermore, no treatment strategies exist at present, but preliminary data suggests that antivirals may prevent
the occurrence of cognitive impairment in PASC.
VHA has established a nationwide COVID-19 cohort early in the pandemic. This objective of this cohort –
called Epidemiology, Immunology and Clinical Characteristics of COVID-19 (EPIC3) – is to characterize the
natural history, clinical outcomes, and the development of immunity while also gathering biospecimens for
future study as questions emerge about this new pathogen. We will leverage the data and samples from this
study to compare participants who received antivirals during their acute COVID-19 illness with those who did
not, by 1) conducting longitudinal cognitive assessments of participants of EPIC3 and characterize trajectories
of cognitive changes, using a novel tablet-based tool; 2) carrying out detailed longitudinal analyses of
biomarkers of neuronal damage, neurodegeneration and blood-brain barrier disruption or participants with and
without COVID-19, and 3) performing advanced structural and functional imaging of a subset of these
participants. We will then correlate biomarkers and imaging findings to the presence, degree and trajectories
of neurocognitive changes in COVID-19 patients who did and did not receive antivirals. We have assembled a
multidisciplinary team with expertise critical to answering the challenging questions posed by neurocognitive
changes of PASC.
Expected findings of our study will have immediate clinical impact: 1) they will establish whether PASC is an
additional goal for antiviral therapy, 2) they will establish a benchmark for standardized, validated assessment
of possible neurocognitive changes in patients with COVID-19; this will provide a basis for future interventions
and management guidelines; 2) determine whether these cognitive changes could be predicted or monitored
using well validated biomarkers of neuronal damage and/or blood-brain barrier disruption; 3) determine
whether structural and function brain imaging could assist in further studies of mechanisms of neuronal
damage and/or neurocognitive dysfunction from COVID-19 infection.
Here we propose addressing current gaps in our understanding of cognitive function in PASC by following the
trajectories of cognitive function over three years using validated, tablet-based neuropsychological tests,
analyzing the relationship between co-morbidities prevalent amongst veterans such as PTSD and depressive
disorders and cognitive impairment following COVID-19. This study will link key neurological and
immunological markers, clinical outcomes, and imaging of cerebral blood flow and demyelination, thereby
contributing a cohesive understanding of the mechanisms of neurological injury.
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